The dramatic anti-cancer activity of protein kinase inhibitors that target specific driver-mutations such as Bcr- Abl, EML4-ALK, mutant EGFR and V600E b-raf is revolutionizing cancer drug discovery. Emerging evidence suggests that abnormal EphA2 kinase activity plays a key role in many types of cancers, including breast, lung, ovary, prostate, glioblastoma, and melanoma as well as a general mechanism of drug resistance to inhibitors of various receptor tyrosine kinases. The Eph system is the largest tyrosine kinase family with 16 RTKs and 9 ligands and has been implicated in a vast array of biological functions ranging from pattern formation during early development to angiogenesis to de-regulation during tumor development. Pharmacological interrogation of the function of specific Eph kinases is currently impossible due to the lack of potent, selective and well- characterized inhibitors. Here we proposed to use a directed-medicinal chemistry approach to develop potent and selective inhibitors of EphA2 and to use these compounds to validate EphA2 as a potential target using cellular and murine models of melanoma and lung cancer. We have identified type I and type II ATP- competitive inhibitors exemplified by 9-14 that exhibit potent activity against EphA2 and other Eph kinases, and here we propose further optimization of potency, selectivity, and pharmacological properties using structure- guided medicinal chemistry (Aims 1&2). The existing and newly generated compounds will be broadly profiled for their antiproliferative activities and, in conjunction with engineered EphA2 drug-resistant alleles will be used to validate EphA2 as a potential target using cellular and murine models of melanoma and lung cancer (Aim 3). Our laboratory has had considerable success in developing first-in-class inhibitors of ALK, Mps1, Erk5, mTor, LRRK2, FGFRs, JNKs, and the T790M mutant form of EGFR and in using these compounds to validate new cancer targets. To accomplish these goals we have assembled a world-class, multidisciplinary team that integrates medicinal chemistry (Gray), structural biology (Knapp), Eph-signaling (Chen), cancer cell biology (Benes, Chen, Tsao), tumor models (Wong, Chen), and clinical care (Tsao) that will enable the development of chemical probes to interrogate EphA2 kinase signaling.

Public Health Relevance

Cancer treatment is being revolutionized by the development of selective drugs that can specifically target the molecular abnormalities of tumors. There is strong biological evidence that inhibiting a protein target named EphA2 will lead to anti-cancer activity. In this proposal we will develop the first proto-type drugs targeting EphA2 to determine whether they will be effective against cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA173469-02
Application #
8643194
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (58))
Program Officer
Forry, Suzanne L
Project Start
2013-03-29
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
2
Fiscal Year
2014
Total Cost
$472,094
Indirect Cost
$196,374
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Amato, Katherine R; Wang, Shan; Hastings, Andrew K et al. (2014) Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC. J Clin Invest 124:2037-49